Ophthalmic disease treatment typically requires either topical administration or intravitreal injection of the particular drug to the eye depending upon the particular disease or condition and the effectiveness of the route of administration with respect to the particular drug and disease. In certain diseases or conditions of the eye effective treatment can only be achieved if the drug is administered by intravitreal injection. There are a litany of diseases and conditions of the eye that are effectively treated by intravitreal injection. At the same time, these injections can cause and/or are associated with serious side effects including eye infections (endophthalmitis), eye inflammation, retinal detachments and increases in eye pressure. Because of these side effects or risks topical treatment of the eye has been both the preferred route of administration of drugs to treat eye conditions and the Holy Grail because in almost all cases, topical administration of the drug does not effectively treat certain eve conditions, especially those conditions that occur in the back of the eye. Thus there is a need to develop formulations that effectively treat said conditions and that eliminate the need to have intravitreal injections. The present inventors believe they have found such a vehicle, U.S. Pat. No. 6,884,879 discloses various anti-VEGF antibodies. This patent specifically describes and claims the monoclonal antibody ranibizumab which is approved and marketed under the brand name LUCENTIS®. The antibodies disclosed therein are described as being capable of preventing, reversing and/or alleviating the symptoms of various diseases and are described as having the ability to inhibit VEGF-induced proliferation of endothelial cells and the ability to inhibit VEGF-induced angiogenesis. LUCENTIS® is approved for neovascular (wet) age-related macular degeneration (AMD) at a dosage strength of 0.5 mg (0.05 mL) by intravitreal injection one a month and, though less effective, the approved treatment may be administered to an injection every three months after an initial regimen of once a month for at least four months. LUCENTIS® is also approved in the United States for macular edema following retinal vein occlusion (RVO) using 0.5 mg (0.05 mL) on a once-a-month intravitreal regimen. In addition, LUCENTIS® is approved in Europe and in the United States for diabetic macular edema in the injectable formulation.
Sunitinib (SU-11248, Sutent), was approved January 2006 by FDA as a monotheraphy for the treatment of metastatic renal cell cancer and gastrointestinal stromal tumors. Sunitinib inhibits at least eight receptor protein-tyrosine kinases including vascular endothelial growth factor receptors 1-3 (VEGFR1-VEGFR3), platelet-derived growth factor receptors (PDGFRα and PDGFRβ). This compound inhibits angiogenesis by diminishing signaling through VEGFR1, VEGFR2, and PDGFRβ. PDGFRβ is found in pericytes that surround capillary endothelial cells 1(Roskosiki 2007, PDF document attached). There is evidence that the combined use of an anti-PDGF is superior to ranibizumab monotherapy in the treatment of some VEGF related diseases.
There are multiple side effects or potential side effects including patient discomfort associated with the intravitreal injection of anti-VEGF antibodies and other ophthalmic drugs. The intravitreal injection procedure requires a dedicated clean room with ordinary aseptic rules; resuscitation facilities must be immediately available. Complications of this procedure include infectious endophthalmitis; retinal detachment and traumatic cataract. Other possible complications of intravitreal injection include intraocular pressure changes, especially intraocular pressure elevations. Injection related intraocular pressure elevations which can occur immediately after injection of any kind of medication and drug specific-related intraocular pressure changes which may be detected days or even months after the injection. See Semin. Ophthamol. 2009 March-April; 24(2):100-5.
There is an urgent unmet medical need for new topical treatment regimens of such anti-VEGF antibodies and other effective ophthalmic drugs such as antimicrobials, antivirals, corticosteroids and anti-vascular endothelial growth factor agents which are the main classes of drugs that are administered through intravitreal injections. The present invention comprises a combination of said Liposomes and any of said drugs within said drug classes in a topical formulation. While U.S. Pat. No. 6,884,879 generally discloses various possible delivery methods or reagents including liposomes and various mutes of administration including topical administration of such VEGF monoclonal antibodies, the only approved form of ranibizumab is the intravitreal form in a liquid formulation. There is a need for topical ranibizumab formulations that are effective in treating people having VEGF related disorders including ophthalmic disorders.
The inventors have met this unmet need and have surprisingly found that certain liposomal formulations comprising such VEGF monoclonal antibodies and certain liposomes provide effective relief in patients having diabetic macular edema. The formulations can be effectively administered topically to the affected eye and are more effective than topical application of the intravitreal formulation. U.S. Pat. No. 6,958,160 discloses and claims self-forming, thermodynamically stable liposomes. U.S. Pat. Pub. No. 2010/0076209, hereby incorporated by reference, discloses PEG-lipid conjugates for liposomes and drug delivery. Various lipid based products including such self-forming thermodynamically stable liposomes marketed under the brand name Qsomes™ (hereinafter Qsome) are sold by Biozone Laboratories for multiple therapeutic uses and via various routes of administration including by topical administration to the skin. The inventors have discovered that a pharmaceutical composition comprising ranibizumab and such self forming, thermodynamically stable liposomes and/or PEG-lipid conjugates can be delivered topically to the eye of a patient in need of treatment of VEGF related ophthalmic diseases and conditions. The present invention further comprises a topical formulation comprising a Qsome as recited herein (self-forming thermodynamically stable liposome) and a drug wherein the formulation is suitable for the treatment of a posterior segment ophthalmic disease and/or a disease that is a combination anterior segment/posterior segment disease. The claimed formulations are suitable for topical administration and are particularly useful in treating ophthalmic diseases and conditions that are typically treated via a periocular route or via intravitreal administration (intraocular delivery). Periocular administration includes subconjunctival, subtenon, retrobulbar and peribulbar administration. There are some drugs that have been disclosed as being able to be delivered to the posterior segment by topical administration-these include ESBA105, an anti-INF-alpha single chain antibody; dexamethasone; nepafenac; memantine HCl; dorzolamide: brimonidine and betaxolol. It is believed that topical administration of these drugs in a Qsome formulation will result in more effective topical delivery and more effective posterior segment delivery. Preferably, however, the claimed invention comprises a topical formulation including a Qsome liposome as described herein and drugs which heretofore have not been effectively delivered through topical administration.
Drugs typically given by intravitreal injection include antimicrobials, antivirals, corticosteroids and anti-vascular endothelial growth factor agents. The present invention comprises a liposomal formulation comprising a self-forming thermodynamically stable liposome and an active pharmaceutical agent selected from any one of or a combination of an antimicrobial, antiviral, corticosteroid and anti-vascular endothelial growth factor agent wherein said formulation is suitable for topical delivery to the eye of a patient to treat an ophthalmic disease or condition. Diclofenac, gatifloxacin, sparfloxcain lactate, GCV, demeclocycline, flubiprofen, doxorubicin, celecoxib, budesonide and cisplatin have been formulated in colloidal dosage forms for transcorneal or transcleral delivery. Cationic liposomes containing penicillin G, tropicamide and acetazolamide have been used to provide maximum drug, transport across the cornea relative to anionic and neutral liposomes. See Schaeffer et al. Liposomes in topical drug deliver. Invest. Ophthalmol. Vis Sci. 198:222(2):220-7; Nagarsenker et al. Preparation and evaluation of liposomal formulations of tropicamide for ocular delivery. Int J Pharma. 1999:190(1)163-71 and Hathout et al. Liposome as an ocular delivery system for acetazolamide: in vitro and in vivo studies. AAPS Pharma Sci Tech. 2007; 8(1):1.
Diabetic retinopathy (DR) is the most common micro-vascular complication of diabetes 2(Fong, 2004) and is the leading cause of new cases of vision loss among working-aged adults. Diabetic macular edema (DME) is the most common cause of vision loss in patients having DR. The prevalence of DME is 3% recent diagnosis with about 75,000 new cases of DME each year (USA). The number of worldwide patients having diabetes is a staggering 285 million. DME results from a series of biochemical and cellular changes that ultimately cause progressive leakage and exudation, leading to thickening of the retina and hard exudates within 1 disc diameter of the center of the macula. DME is one of the most common causes of impaired vision in patients with diabetes 3(Bhagat, 2009). Approximately 50% of patients experience a loss of ≥2 lines of BCVA after two years of follow-up 4(Meyer, 2007).
In DME, damaged blood vessels leak fluid into the central portion of the retina (macula) which leads to swelling. The macula is involved with sharp central vision. The fovea is at the center of the macula. DME can occur in patients having type 1 or type 2 diabetes. Approximately 26 million people in the United States have diabetes and 1.9 million new cases are diagnosed in people aged 20 and older each year. Up to 75,000 new cases of DME are estimated to develop each year. DME is a leading cause of blindness among the working-age population in most developed countries. First line therapy for DME is laser surgery which seals the leaky blood vessels to diminish the leakage of fluid and reduce the amount of fluid in the retina. There is thus a significant need to create new formulations that provide therapeutic relief to these patients.